PROJECT SUMMARY/ABSTRACT There is strong comorbidity between alcohol use disorders and chronic stress and anxiety. Dysfunction within overlapping neural targets of alcohol and stress may facilitate the development of this comorbid phenotype. The locus coeruleus norepinephrine (LC-NE) system is sensitive to both alcohol and stress and plays an important role in cognitive and emotional regulation of behavior. Plasticity within LC-NE circuits after chronic stress and alcohol can produce feed-forward effects, elevating stress and anxiety via the HPA axis and decreasing cognitive control by disrupting prefrontal cortex (PFC) function. The consequence of this stress- cognition ?double-hit? is an increased need to drink and a decreased control over drinking. Our preliminary evidence demonstrates that chronic intermittent ethanol exposure in addition to repeated swim stress, disrupts PFC dependent cognition and increases excessive drinking more than either ethanol or stress alone. In these studies we will investigate the LC as a key target of stress/ethanol maladaptations and the potential for LC-NE targeted therapeutics to ameliorate stress/ethanol induced executive dysfunction, elevated anxiety, and excessive drinking. This project will provide new insights into the role of LC-NE dysfunction after chronic stress and alcohol. Our results will identify novel circuit changes underlying excessive alcohol consumption and the potential for NE targeted therapies in treating cognitive and emotional dysfunction in alcohol use disorders.